Performance of LFSPRO TP53 germline carrier risk predictions compared to standard genetic counseling practice on prospectively collected probands

Genetic counseling and testing for germline mutations are essential for identifying individuals at increased risk for cancer. Pathogenic variants in TP53 are diagnostic of Li-Fraumeni syndrome (LFS), a highly penetrant disorder with diverse, early-onset tumors. Current clinical guidelines, such as Chompret and Classic criteria, provide frameworks for identifying individuals at risk for likely pathogenic/pathogenic TP53 variants; however, genetic counselors often encounter patients with features concerning for LFS that do not clearly meet established criteria, creating challenges for risk assessment and testing decisions. We evaluated whether LFSPRO, a Mendelian, family-history-based model that estimates the individual’s probability of harboring a deleterious TP53 variant, improves carrier identification relative to guideline criteria. In a prospectively collected cohort of 182 probands who underwent clinical genetic counseling and germline TP53 testing, LFSPRO showed superior discrimination compared with Chompret criteria, with higher sensitivity (81% vs. 33%) and specificity (88% vs. 65%) and improved predictive values (PPV 0.53 vs. 0.14; NPV 0.96 vs. 0.85). Receiver operating characteristic analysis confirmed strong discriminatory performance (AUC=0.88). Calibration analysis using observed-to-expected ratios indicated good agreement between predicted and observed carrier frequencies (Observed/Expected=1.07). These findings demonstrate that LFSPRO outperforms traditional guideline-based criteria for identifying TP53 mutation carriers in real-world clinical settings. By providing quantitative, well-calibrated carrier probabilities rather than binary classifications, LFSPRO can enhance genetic counseling and support testing decisions, particularly for individuals who do not clearly meet existing criteria. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by the Cancer Prevention and Research Institute of Texas [RP200383] and the National Institutes of Health [R01CA239342, P30CA016672]. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Office of Human Subject Protection/IRB of The University of Texas MD Anderson Cancer Center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes

updated for a better understanding; Results updated for visualization; Conclustion updated Data Availability All data produced in the present study are available upon reasonable request to the authors